chr4-99608827-G-A

Position:

chr4-99608827-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001386140.1(MTTP):c.1619G>A(p.Arg540His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

MTTP
NM_001386140.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 9.37

Variant links:

Genes affected

MTTP (HGNC:7467): (microsomal triglyceride transfer protein) MTP encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein. Protein disulfide isomerase (PDI) completes the heterodimeric microsomal triglyceride transfer protein, which has been shown to play a central role in lipoprotein assembly. Mutations in MTP can cause abetalipoproteinemia. [provided by RefSeq, Jul 2008]

MTTP links:

ENSG00000248676 (HGNC:):

ENSG00000248676 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 4-99608827-G-A is Pathogenic according to our data. Variant chr4-99608827-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99608827-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTTP	NM_001386140.1 linkuse as main transcript	c.1619G>A	p.Arg540His	missense_variant	12/18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 linkuse as main transcript	c.1619G>A	p.Arg540His	missense_variant	13/19		NP_000244.2	P55157-1
MTTP	NM_001300785.2 linkuse as main transcript	c.1370G>A	p.Arg457His	missense_variant	12/18		NP_001287714.2	P55157B7Z7X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MTTP	ENST00000265517.10 linkuse as main transcript	c.1619G>A	p.Arg540His	missense_variant	12/18	1	NM_001386140.1	ENSP00000265517.5	P55157-1
MTTP	ENST00000457717.6 linkuse as main transcript	c.1619G>A	p.Arg540His	missense_variant	13/19	5		ENSP00000400821.1	P55157-1
MTTP	ENST00000511045.6 linkuse as main transcript	c.1370G>A	p.Arg457His	missense_variant	12/18	2		ENSP00000427679.2	E9PBP6
ENSG00000248676	ENST00000508578.1 linkuse as main transcript	n.128+12060C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251154

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Abetalipoproteinaemia

Pathogenic:4Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 03, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 22, 1996	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2022	Variant summary: MTTP c.1619G>A (p.Arg540His) results in a non-conservative amino acid change located in the Vitellogenin, N-terminal (IPR039988) of the encoded protein sequence, specifically within the alpha-helical region (Khatun_2013). Another missense variant affecting the same amino acid has been classified as likely pathogenic by our laboratory (c.1618C>T, p.Arg540Cys), providing moderate evidence of pathogenicity. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251154 control chromosomes. c.1619G>A has been reported in the literature in individuals affected with Abetalipoproteinaemia (Rehberg_1996, Wang_2000, Di Filippo_2019), with evidence of co-segregation in two families. Some individuals are reported as compound heterozygous, carrying other variants in trans likely to be pathogenic. These data indicate that the variant is likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on protein function, showing R540H loses phospholipid and triglyceride transfer activities and the ability to support apoB secretion (Rehberg_1996, Khatun_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, both classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 540 of the MTTP protein (p.Arg540His). This variant is present in population databases (rs199422220, gnomAD 0.003%). This missense change has been observed in individual(s) with abetalipoproteinemia (PMID: 8939939, 10679949, 30522860). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 14238). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTTP protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MTTP function (PMID: 8939939, 23475612). This variant disrupts the p.Arg540 amino acid residue in MTTP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25108285, 27578136). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

.;D;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.0

.;M;M

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

1.0

MVP

0.89

MPC

0.87

ClinPred

1.0

GERP RS

4.9

Varity_R

0.77

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over